Shakur Yasmin, Fong Miranda, Hensley James, Cone James, Movsesian Matthew A, Kambayashi Jun-Ichi, Yoshitake Masuhiro, Liu Yongge
Otsuka Maryland Research Institute, 9900 Medical Center Drive, Rockville, MD 20850, USA.
Cardiovasc Drugs Ther. 2002 Sep;16(5):417-27. doi: 10.1023/a:1022186402442.
We investigated the basis for the difference in the cardiotonic effects of the PDE3 inhibitors cilostazol and milrinone in the rabbit heart. Cilostazol displayed greater selectivity than milrinone for inhibition of cAMP-PDE activity in microsomal vs cytosolic fractions from rabbit heart. This difference was due to the inhibition of significantly less cytosolic cAMP-PDE activity by cilostazol compared to milrinone. A combination of cilostazol (>15 microM) and the PDE4 selective inhibitor, rolipram (5 microM), inhibited levels of cytosolic cAMP-PDE activity similar to those inhibited by milrinone on its own. This suggested that milrinone inhibited PDE4 in addition to PDE3 activity. In isolated rabbit cardiomyocytes, milrinone (>10 microM) caused greater elevations in intracellular cAMP and calcium than cilostazol. In the presence of rolipram, however, the cAMP and calcium elevating effects of cilostazol and milrinone were similar. Therefore, in rabbit heart, partial inhibition of PDE4 by milrinone contributed to greater increases in cardiomyocyte cAMP and calcium levels than cilostazol. PDE4 activity in failing human heart was lower than in rabbit heart and there was no significant difference in the inhibition of human cytosolic cAMP-PDE by cilostazol and milrinone. Our results suggest that in normal rabbit heart inhibition of PDE4 by milrinone may partly contribute to the greater cardiotonic effect of milrinone when compared to cilostazol. However, the lower level of PDE4 activity in failing human heart suggests that factors other than inhibition of PDE4 by milrinone may contribute to differences in cardiotonic action when compared to cilostazol.
我们研究了磷酸二酯酶3（PDE3）抑制剂西洛他唑和米力农对兔心脏强心作用差异的基础。与米力农相比，西洛他唑对兔心脏微粒体和胞质部分中环磷酸腺苷-磷酸二酯酶（cAMP-PDE）活性的抑制表现出更高的选择性。这种差异是由于与米力农相比，西洛他唑对胞质cAMP-PDE活性的抑制作用明显较弱。西洛他唑（>15微摩尔）与PDE4选择性抑制剂咯利普兰（5微摩尔）联合使用时，对胞质cAMP-PDE活性的抑制水平与米力农单独使用时相似。这表明米力农除了抑制PDE3活性外，还抑制PDE4。在分离的兔心肌细胞中，米力农（>10微摩尔）比西洛他唑引起细胞内cAMP和钙的升高幅度更大。然而，在咯利普兰存在的情况下，西洛他唑和米力农对cAMP和钙的升高作用相似。因此，在兔心脏中，米力农对PDE4的部分抑制作用导致心肌细胞cAMP和钙水平的升高幅度比西洛他唑更大。衰竭的人类心脏中的PDE4活性低于兔心脏，西洛他唑和米力农对人胞质cAMP-PDE的抑制作用没有显著差异。我们的结果表明，在正常兔心脏中，与西洛他唑相比，米力农对PDE4的抑制作用可能部分导致了其更强的强心作用。然而，衰竭的人类心脏中较低的PDE4活性表明，如果与西洛他唑相比，米力农对PDE4的抑制作用以外的因素可能导致强心作用的差异。
